The combination has the potential to treat different types of childhood cancer, including osteosarcoma, leukemia and neuroblastoma, while possibly sparing young patients from more difficult therapies such as stem cell transplant or more toxic chemotherapy.

Dean Lee, M.D., Ph.D., assistant professor of pediatrics from the Children's Cancer Hospital at M. D. Anderson, has found that combining the epigenetic drug MS-275 with natural killer (NK) cells makes osteosarcoma cells more sensitive to NK cells while making the NK cells more lethal to the tumor, as presented at the American Society of Pediatric Hematology/Oncology annual meeting on May 15.

"Traditional chemotherapy drugs kill any fast-growing cells like cancer, but they also killed healthy fast-growing cells like hair, bone marrow and mucous membranes, making the drugs very toxic," says Lee, senior investigator on the study. "There's a new class of drugs that takes cells that aren't properly regulated and makes them behave. In our study, we found that these drugs make tumor cells more recognizable and vulnerable to natural killer cells."

Osteosarcoma is a rare pediatric cancer, but the most common bone cancer found in children. According to the American Cancer Society, it affects approximately 400 children, adolescents and young adults under the age of 20 in the United States each year, and nearly a third of those relapse. Relapsed and metastatic osteosarcomas are rarely sensitive to treatment with chemotherapy or radiation, but several studies have suggested these tumors may be immunologically responsive.

Lee's study of human tissue cultures shows the synergistic effect of combining NK cells with histone deacetylase (HDAC) inhibitors such as MS-275 to fight childhood cancer, which Lee hopes will lead to a clinical trial for patients. When added to a human tissue culture, MS-275 heightened the amount of the NKG2D receptor on the NK cell's surface to pick up signals from stressed cells, such as tumor cells. In addition, the MS-275 simultaneously caused the stress signals of the tumor cells to increase, making it easier for NK cells to detect them and kill them.

Trials are currently open using HDAC and proteasome inhibitors as well as NK cells to treat patients, but not as a combination therapy.

"By applying what we've found from our study, we hope to improve our treatment for many cancers, but not by giving more NK cells or by giving more toxic chemotherapy," says Lee. "Instead, we want to marry the two therapies to improve each other and provide a more effective, less toxic treatment for our patients."

Lee's study found similar responses from acute myelogenous leukemia (AML) and neuroblastoma, but using different inhibitors. For neuroblastoma and AML, the proteasome inhibitors Bortezomib and NPI-0052 were found to have the greatest effect on sensitizing tumor cells to NK cells. Additional research is being conducted on acute lymphocytic leukemia, the most common cancer in children, and medulloblastoma, the most common brain cancer in children.

Other investigators on the study include Shiguo Zhu, Ph.D, and Laurence Cooper, M.D.